COPD is a major and increasing global health problem, which is currently the fourth most common cause of death and is predicted to become the fifth most common cause of chronic disability in the next few years. Despite recognition as an increasingly important international health problem, current treatments for COPD are inadequate, owing in part to a fundamental lack of knowledge about the cellular, molecular and genetic causes of COPD.
The mechanisms leading to increased airway inflammation in COPD patients are complex, and in contrast to asthma, may not be inhibited by corticosteroid treatment. It has been observed that HDAC2 transcription levels, as well as HDAC2 protein expression, are reduced in severe COPD patients, particularly in the lungs, airways, and alveolar macrophages of those patients. Without being bound by theory, it is believed herein that the reduced levels may be due to proteasomal degradation. In addition, it has been discovered that oxidative stress and hypoxic condition may reduce HDAC2 promoter activation. It has also been discovered that the reduction of promoter activity or HDAC activity under oxidative stress may be normalized by phosphoinositide-3-kinase (PI3K) inhibitors and Akt inhibitors. It has also been discovered that the expression of specific inflammatory genes is increased, including CXC chemokines, such as IL-8 and GRO-α, TNF-α, and matrix metalloproteinase-9 (MMP-9). Further, it has been discovered that the reduced HDAC2 activity and expression may lead to both the observed increased expression of inflammatory genes and the decreased response to corticosteroids (see, e.g., Ito et al., N Engl J Med (2005); Ito et al., J Exp Med (2006)). The disclosure of the foregoing publication, and each publication cited herein, is incorporated herein by reference.
In laboratory tests, it has been reported that H2O2 treatment induces corticosteroid insensitivity on TNF-α-induced IL-8 production in a human macrophage cell line (U937 cells). Erythromycin has been reported to restore corticosteroid sensitivity. Erythromycin has also been reported to restore corticosteroid sensitivity seen in peripheral blood mononuclear cells (PBMCs) obtained from COPD patients. Furthermore erythromycin inhibited MMP9 expression in macrophages present in the sputum of COPD patients. Erythromycin has also been reported to restore HDAC2 promoter activity and protein expression that are reduced by oxidative stress. However, erythromycin has been reported to lack sufficient in vivo efficacy.
In addition, it is appreciated herein that the chronic treatment that would be necessary to treat patients suffering from COPD and other inflammatory diseases may not amenable to the use of erythromycin, and other compounds with substantial antibacterial or antibiotic activity, due to the potential for resistance development by bacteria and other pathogens against those compounds.
It has been discovered herein that compounds described herein are useful in treating inflammatory diseases. In one illustrative and non-limiting embodiment of the invention, compounds, compositions, and methods are described herein for treating and/or prevention of inflammatory diseases. Illustrative inflammatory diseases include, but not limited to, chronic obstructive pulmonary disease (COPD), including late-stage COPD, asthma, rheumatoid arthritis (RA), inflammatory bowel disease, chronic bronchitis, emphysema, septic shock, ulcerative colitis, Crohn's disease, adult or acute respiratory distress syndrome (ARDS), psoriasis, and the like. In another embodiment, compounds, compositions, and methods are described for treating and/or prevention of inflammatory diseases of the respiratory system.
It has been discovered herein that compounds described herein are capable of restoring HDAC2 activity. Without being bound by theory, it is believed herein that compounds described herein may increase HDAC promoter activity, may restore expression levels of HDAC2 and/or may decrease degradation of HDAC protein, such as degradation by proteosomes. It has also been discovered that compounds described herein decrease the production of inflammatory and proinflammatory agents, such as but not limited to IL-2, IL8, TNF-alpha, MMP-9, and the like, including HDAC mediated production of such inflammatory and proinflammatory agents.
It has also been discovered herein that compounds described herein are capable of reversing corticosteroid insensitivity, such as corticosteroid insensitivity that is observed in patients having inflammatory diseases that are being treated with corticosteroids, including patients being treated inflammatory diseases of the respiratory system such as COPD. In another embodiment, compounds, compositions, and methods are described for treating and/or prevention of inflammatory diseases in patients exhibiting corticosteroid insensitivity. In one variation, cotherapies for treating and/or prevention of inflammatory diseases in patients being treated with a corticosteroid are described that include the compounds, compositions, and methods described herein. In another embodiment, the disease is asthma. In another embodiment, the disease is rheumatoid arthritis. In another embodiment, the disease is COPD, including late stage COPD.